1. Area of the Art
This invention relates to a lithium ion-selective electrode for a potentiometric determination of a lithium ion concentration in liquid samples, particularly in clinical samples.
2. Description of the Prior Art
The use of lithium has become a widely accepted treatment of mental disorders, such as maniac depressive illness. Due to its toxicity, close monitoring of lithium concentration in biological fluids (e.g. sera, plasma, urine, spinal fluid, or whole blood) is required during the treatment. However, quantitative determination of lithium is hampered by the presence of other ionic compounds, in particular sodium ions, in such fluids. This interference is most noticeable at lower lithium concentrations (for example, about 0.10 mmol/l). Accordingly, there is a need for a convenient and highly sensitive method for a quantitative lithium analysis in clinical samples.
Various techniques and methods for the quantitative determination and measurement of lithium in a liquid test medium are known, but have been limited in the past, for the most part, to flame photometry. Despite its relative simplicity, flame photometry is a tedious procedure with high susceptibility to background interferences. Additionally, flammable gas utilized in this method presents a safety concern.
A potentiometric determination of a lithium ion concentration in clinical samples avoids many of these problems. Typically, devices for potentiometric measurements of lithium ion include a reference electrode and a lithium ion-selective electrode (Li-ISE). When the electrodes are simultaneously immersed into a sample solution, an electrical potential develops between them. This potential is proportional to the logarithm of the activity of the lithium ion. The logarithmic relationship between the potential and ionic activity in solution is described by the well-known Nernst equation. The electrical potential can be determined using a potentiometric measuring device, such as an electrometer.
Currently available Li-ISEs typically include a lithium ion-selective membrane formed of a lithium ion-selective carrier (lithium ionophore), an activator, a film-forming polymeric resin, and a plasticizer. The ionophore must be capable of sequentially complexing the lithium ion, transporting the complexed ion across the membrane, and releasing the ion, in preference to other cations present in the sample solution. Examples of such ionophores include crown ethers such as 14-crown-4-derivatives and 15-crown-4-derivatives (J. Am. Chem. Soc., 106 (1984), p. 6978), amide ethers (Anal. Chem., 58 (1986), p. 1948); polypropoxylate adducts (Analyst, 110 (1985), p. 1381); N,Nxe2x80x2-diheptyl-N, Nxe2x80x2-5,5-tetramethyl-3,7-dioxsanonane diamide (Helv. Chim. Acta, 69 (1986), page 1821 and J. Chem. Soc. Perkin Trans., II, (1986), p. 1945), a derivative of 1,10-phenanthroline (U.S. Pat. No. 4,861,455), and the like.
U.S. Pat. Nos. 4,214,968; 4,504,368; 4,770,759 describe Li-ISEs utilizing crown ethers as ionophores. However, many crown ethers are not adequately selective to lithium ions. For example, 1,5,9,13-tetramethyl-1,5,9,13-tetranonyl tetrafuro-16-crown-4-ether and dicyclohexyl-12-crown-4-ether exhibit unacceptable electrode drift and poor ion selectivity when used as lithium ionophores (U.S. Pat. No. 4,504,368). Therefore, selection of an ionophore and its concentration, and optimizing amounts of other additives in the membrane of Li-ISE are important for the optimum performance of the electrode (Anal. Chem. Acta, (1984), 156, p. 1).
The conventional Li-ISEs have significant limitations, including short lifetime and poor reproducibility. Conventional Li-ISEs lose their sensitivity and reliability, even with the most carefully preformed conditioning procedures, and start to exhibit non-Nernstian responses and substantial random drift. Another major drawback of currently available Li-ISE is their limited specificity (Anal. Chem. (1991), 63, p. 22850). This represents a major problem in view of 130-150 mmol/l of sodium typically present in patient serum and plasma samples. Protein, present in biological samples, also hinders performance of conventional Li-ISE membranes.
Conventional Li-ISEs, therefore, fail to provide ion-selective compositions and electrodes which are highly selective and sensitive to lithium ion, accurate, and long-lasting.
It is an object of the present invention to provide a novel Li-ISE membrane having high selectivity and specificity for lithium ions, fast kinetic response, good measuring precision, and a long life-time. It is a further object of the invention to provide a Li-ISE which retains sensitivity, precision, Nernst linearity, and reproducibility after long-term contact with biological samples and in the presence of competing species, such as sodium.
These and other objects are achieved in a lithium ion-selective membrane of the present invention comprising at least about 2% by weight of 6,6-dibenzyl-1,4,8, 11 tetraoxacyclotetra-decane ionophore and from about 0.05% to about 1% by weight of a potassium tetrakis(4-chlorophenyl) borate additive. The composition of the membrane further includes a plasticizer and a polymeric material.
The Li-ISE of the present invention has been found to provide a number of advantages. As explained in a greater detail below, these advantages include negligible affect of sodium and proteins present in the samples on measurements, even after exposure to more than 20,000 patient samples, fast response, and Nernst linearity of the signal at low lithium concentrations. The Li-ISE of this invention has a long life-time.
The Li-ISE of this invention system is well-suited for use with any analytical system, which relies on potentiometric determinations of lithium ion in fluids. Examples of such systems include, but are not limited to, SYNCHRON EL-ISE, SYNCHRON CX, and SYNCHRON LX20 clinical systems manufactured by Beckman Coulter, Inc. (CA).
The present invention is defined in its fullest scope in the appended claims and is described below in its preferred embodiments.